The Middle Interhemispheric Variant of Holoprosencephaly

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The Middle Interhemispheric Variant of

Holoprosencephaly

Erin M. Simon, Robert F. Hevner, Joseph D. Pinter, Nancy J. Clegg, Mauricio Delgado,

Stephen L. Kinsman, Jin S. Hahn, and A. James Barkovich

BACKGROUND AND PURPOSE: The middle interhemispheric variant of holoprosencephaly

(MIH) is a rare malformation in which the cerebral hemispheres fail to divide in the posterior

frontal and parietal regions. We herein describe the structural abnormalities of the brain in a

large group of patients with MIH, compare these features with those of classic holoprosen-

cephaly (HPE), and propose a developmental mechanism, based on current knowledge of

developmental neurogenetics, by which MIH develops.

METHODS: Brain images obtained in 21 patients with MIH (MR images in 16 patients and

high-quality X-ray CT scans in five patients) were retrospectively reviewed to classify cerebral

abnormalities. The cerebral parenchyma, hypothalami, caudate nuclei, lentiform nuclei, thalami,and mesencephalon were examined for the degree of midline separation (cleavage) of the two hemi-

spheres. The orbits, olfactory apparati, and presence or absence of a dorsal cyst were also assessed.

RESULTS: In all patients, by definition, midportions of the cerebral hemispheres were

continuous across the midline, with an intervening interhemispheric fissure. The sylvian

fissures were abnormally connected across the midline over the vertex in 18 (86%) of 21

patients. Two patients had relatively normal-appearing sylvian fissures; one had unilateral

absence of a sylvian fissure owing to substantial subcortical heterotopia. Heterotopic gray

matter or dysplastic cerebral cortex was also seen in 18 (86%) of 21 patients. MIH differed from

classic HPE as follows. 1) In all subjects, the midline third ventricle separated the hypothal-

amus and lentiform nuclei. 2) The caudate nuclei were separated by the cerebral ventricles in

17 (89%) of the 17 patients in whom they could be assessed. 3) The most commonly affected

basal nucleus was the thalamus (non-cleavage in seven [33%] of 21 cases, abnormal alignment

in 1 [5%]). 4) Three (18%) of the 16 patients in whom the mesencephalon could be assessedshowed some degree of mesencephalic non-cleavage. 5) No patients had hypotelorism (four had

hypertelorism, the remainder manifested normal intraocular distances). Dorsal cysts were

present in five (25%) of the 20 patients in whom they could be assessed (dorsal cysts could not

be assessed after shunt surgery), and as in classic HPE, were associated with severe thalamic

non-cleavage in three of these five patients.

CONCLUSION: MIH appears to cause non-cleavage of midline structures in a completely

different pattern than does classic HPE. In MIH, impaired induction or expression of genetic

factors appears to influence the embryonic roof plate, whereas in classic HPE, induction or

expression of the embryonic floor plate seems to be affected.

The middle interhemispheric variant of holoprosen-

cephaly (MIH) was first described in 1993 (1). Alsoreferred to as syntelencephaly, this malformation

consists of an abnormal midline connection of the

cerebral hemispheres in the posterior frontal and pa-rietal regions, with interhemispheric separation of the

Received September 18, 2000; accepted after revision August 1,2001.

From Departments of Diagnostic Radiology (E.M.S., A.J.B.)and Psychiatry (R.F.H.), University of California, San Francisco;Department of Neurology (J.D.P., J.S.H.), Stanford University,Stanford, CA; Department of Neurology (N.J.C., M.D.), TexasScottish Rite Hospital for Children, Dallas, TX; and Departmentof Neurology (S.L.K.), Kennedy Krieger Institute, Baltimore, MD.

American Society of Neuroradiology

Funded in part by the Carter Centers for Brain Research inHoloprosencephaly and Related Malformations; J.D.P. supportedby NIH Grant No. K12 NSO1692.

Presented at the 39th Annual Meeting of the American Societyof Neuroradiology, Boston, MA, April 2001.

Address reprint requents to Erin M. Simon, MD, OTR, Depart-ment of Radiology, The Childrens Hospital of Phildelphia, 34th St.and Civic Center Blvd., Philadelphia, PA 19104-4399.

AJNR Am J Neuroradiol 23:151155, January 2002

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basal forebrain, anterior frontal lobes, and occipitalregions. Since the first report, additional case reportsand small series describing this unusual malformationhave appeared in the literature (25). To our knowl-edge, however, no investigation assessing structuralabnormalities in MIH in a large patient series hasbeen published. A detailed analysis of MIH and acomparison of its features with those of classic forms

of holoprosencephaly (HPE) (recently reported indetail in two large series [6, 7]) could be valuablein clarifying the underlying developmental processesin both. Briefly, three classic forms of HPE have beendescribed. Alobar HPE, the most severe of the threetypes, generally appears as a pancake-like mass ofcerebral tissue and a crescentic monoventricle. Semi-lobar HPE is characterized by non-cleaved anteriorbrain, with the posterior falx and posterior interhemi-spheric fissure (IHF) present. Lobar HPE is alsocharacterized by anterior brain non-cleavage that ex-ists to a lesser degree than that of semilobar HPE, afully formed third ventricle, and some development offrontal horns of the lateral ventricles (8 10).

Herein we provide a detailed analysis of brain im-ages obtained in 21 patients with MIH, compare thesefindings with those observed in classic HPE, and cor-relate these data with the most current informationregarding the genetic factors controlling early braindevelopment. Our focus centers on those regions ofthe developing brain involved in dorsal-ventral andmedial-lateral patterning.

MethodsBrain images were retrospectively selected from a group of

patients referred to The Carter Centers for Brain Research inHoloprosencephaly and Related Malformations as well as fromthose patients referred to us at our respective institutions. The

Carter Centers is a national consortium funded by a not-for-profit foundation, with its primary clinical research and treat-ment center at the Texas Scottish Rite Hospital for Children(Dallas, TX). A total of 121 brain images were retrospectivelyreviewed by two neuroradiologists (E.M.S., A.J.B.). One hun-dred of these patients manifested classic HPE according tostandard definitions (8 10), and a subset of these has beenreported on previously (6, 7). MIH was diagnosed in the re-maining 21 patients (age range, 1 day to 4 years old). Two ofthese cases have been described in an earlier publication (1).

All 21 patients had adequate imaging studies for assessmentof most of the components of the malformation spectrum. Theimages that were used included MR images obtained in 16patients and high-quality X-ray CT scans obtained in five pa-tients. Because images were obtained at multiple institutionson a variety of imaging systems, techniques varied considerably.

All MR imaging included sagittal T1-weighted sequences andat least one examination in the axial plane with either a T1- orT2-weighted sequence. Coronal sections were available in 14patients. Paramagnetic contrast agent was not routinely admin-istered. CT scans were only obtained in the axial plane and nocontrast agent was used.

The caudate nuclei, lentiform nuclei, thalami, and thalamicorientation were graded according to a previously presentedscale (6). The sylvian fissures were analyzed with respect tolocation and orientation. The portions of the corpus callosumthat were present were documented, as determined by assuringthat the commissure connected neocortical white matter ofeach hemisphere. Three of the five CT scans allowed adequateassessment of the callosal genu and spenium. The callosal body,

which parallels the image plane on axial images, cannot beaccurately assessed by CT alone.

The intraocular distance (IOD) was determined by correlat-ing the interpupillary distance (IPD) and bony interorbitaldistance (BIOD) with patient age (11). The presence or ab-sence of the olfactory sulci and bulbs was noted; if present,subjective determination of normal versus reduced size wasmade. The structure of the cerebellum was subjectively as-sessed.

When visible, the arteries of the anterior cerebral circulationwere evaluated for alterations in pattern, particularly the pres-ence of an azygous anterior cerebral artery. Also, when imagingallowed, the pituitary gland was subjectively graded as normalor abnormal in size and signal intensity for age (12).

Results

The sylvian fissures were abnormally connectedacross the midline over the vertex in 18 (86%) of 21patients. Two patients had relatively normal-appear-ing sylvian fissures; one had no right sylvian fissureowing to a large subcortical heterotopia. Heterotopicgray matter or cortical dysplasia were also seen in 18

of 21 cases that were not necessarily associated withabnormal sylvian fissures, including abnormal thick-ening of the cortex lining the anterior IHF. Reducedsulcation (ie, the normal cingulate sulci and internalfrontal sulci were absent) in 15 (71%) of the 21patients (Figs 1 and 2).

The hypothalamus and lentiform nuclei appearednormally separated in all patients. The caudate nuclei

were incompletely separated in two (11%) of the 19patients in whom they could be adequately assessed,

whereas the thalami could be visualized in all 21patients and were incompletely separated in seven(33%) (Fig 3). The thalami were abnormally oriented,

with their long axes nearly parallel, in only one (5%)

patient. The mesencephalon appeared incompletelyseparated from the diencephalon in three (18%) ofthe 17 patients in whom this could be assessed. Dorsalmidline cysts were present in five (25%) of 20 MIHpatients in whom it could be assessed (could not beassessed if images were acquired after shunt surgery)and was associated with severe thalamic non-cleavagein three of these five patients.

Some component of the corpus callosum waspresent in all 18 patients in whom the corpus could bereasonably assessed (assessment was not possible inthree patients who had only undergone CT scanning).The splenium and genu were identified in 11 (61%) of18 (Fig 4). Four (22%) of these 18 patients had either

a splenium or genu (but not both structures), andthree (19%) of the 16 patients who underwent MRimaging had some portion of the body present inaddition to the splenium of the callosum or genu ofthe callosum or both. No patient had a completecorpus callosum.

Analysis of the orbits revealed a normal IOD in 13(77%) of the 17 patients in whom it could be accu-rately examined. Four patients had hypertelorism(IPD and BIOD at or above the 97th percentile forage). It was also noted that, in those with a normalIOD, all patients were at or above the 50th percentile

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for age. No patients had hypotelorism. In 12 (92%) of13 of the cases in which it could be assessed, the opticchiasm was normal in appearance. One patient had asmall (presumably hypoplastic) chiasm.

The anterior cerebral arterial circulation patterncould be adequately assessed in 16 of our 21 patients.In all 16 patients, the anterior cerebral artery wasunpaired (azygous), whereas the middle cerebral ar-

tery trunks appeared normal.The inferior frontal lobes could be assessed in the

coronal plane in 14 cases, allowing for the evaluationof the olfactory sulci in all 14 and the olfactory bulbsin 11. Olfactory sulci were present and normal inconfiguration in eight (57%) of 14 cases. The remain-der were absent (2) or present but shallow (presum-ably hypoplastic) (4). Olfactory bulbs appeared nor-mal in size and location in seven (64%) of 11 cases(all seven with normal olfactory sulci) (Fig 5). Theremaining four appeared small.

Two (10%) of the 21 patients were noted to have

cephaloceles overlying the bridge of unseparatedparenchyma. One was atretic, whereas the other

was large and required surgical intervention (Figs 2and 4).

Abnormalities of the cerebellum were present infour (19%) of 21 patients, including Chiari I and IImalformations, cerebellar hypoplasia, and inferior

vermian hypogenesis (Fig 2).

Sagittal and coronal MR imaging allowed exami-nation of the pituitary gland in 16 patients. The gland

was seen in all patients; it was normal in 12 andsubjectively small in four.

Discussion

This analysis of 21 patients suggests that the com-ponents of the MIH malformation differ substantiallyfrom those seen in classic HPE. The relative sparingof the basal forebrain with a well-formed anteriorIHF, the greater involvement of the thalami than that

FIG 1. Axial T1-weighted image (550/14/2 [TR/TE/excitations]) in the posterior frontal and pari-etal regions shows the abnormal sylvian fissurescommunicating across the midline over the ver-tex (black arrows). Flow-related enhancement isseen within branches of the middle cerebral ar-teries, confirming that this represents the sylvianfissure. Thickened dysplastic cortex is presentalong the anterior IHF (white arrows).

FIG 2. Coronal echo-planar inversion recov-ery image (2000/30/400 [TR/TE/TI]) depicts thelarge area of subcortical dysplasia and associ-ated gray matter heterotopia (white arrows).The site of the repaired cephalocele can beseen at the vertex (black arrows). The inferiorvermis is absent.

FIG 3. Axial spin-echo T2-weighted image (2530/80/2 [TR/TE/excitations]) shows the widely separated deep gray nuclei (arrows),unlike those seen in classic HPE.

FIG 4. Sagittal T1-weighted image (400/15/1) through the midline reveals the genu and splenium of the corpus callosum (black arrows).The body of the callosum is absent in the region of non-cleaved parenchyma. An atretic cephalocele is also present (white arrow). Notealso that the anterior recess of the third ventricle and basal forebrain are normal, unlike that seen in classic HPE.

FIG 5. Coronal fast spin-echo T2-weighted image (3200/117/1) through the inferior frontal lobes depicts the normal appearance of theanterior IHF, olfactory sulci (black arrows), and olfactory bulbs (white arrows).

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in the caudates and hypothalami, the different loca-tions of callosal involvement, and the overwhelminglynormal IOD and optic chiasm formation all suggestthat MIH either has a different embryogenetic mech-

anism than that of classic HPE or has a similar mech-anism that acts at a different location.

However, both MIH and classic HPE share a fun-damental similarity: non-cleavage of a substantialportion of the supratentorial brain into two separatehemispheres. In addition, several other features areseen in both MIH and classic HPE, including theabnormalities of the anterior arterial circulation andsylvian fissure structure. Thus, it seems that someunderlying similarity must exist in the mechanisms by

which these malformations develop.Some insight into the embryologic development of

MIH was provided by the recent discovery that one ofthe patients included in this study has a mutation of the

ZIC2 gene. The human ZIC2 gene encodes a zinc fin-ger transcription factor, a DNA-binding, gene-spe-cific factor that consists of 28 amino acid repeats,each sequence folded around a zinc ion (13). Studiesof the homologous mouse gene, Zic2, have indicatedthat Zic2 plays important roles in neural tube closureand in differentiation of the roof plate of the devel-oping embryo (Fig 6). In mice, mutation of Zic2results in defects of neural tube closure and HPE.Both of these defects seem to result from impairedexpression of roof platespecific properties, such asdecreased mitotic rate and increased apoptotic rate

(14). The reduction of mitotic rate and increase ofapoptosis in the roof plate are critical to the forma-tion of the IHF. Thus, mutation ofZic2 may result ina continuum of cerebral tissue across the midline ofthe dorsal cerebrum, without an intervening IHF (Fig6), precisely the structural appearance of MIH.

In contrast to other genes that have been linked toHPE (eg, Sonic hedgehog), ZIC2 is not involved in

patterning of the embryonic dorsoventral axis butinstead acts in the dorsal midline to promote differ-entiation of the roof plate. This difference may ex-plain the absence of craniofacial malformations andthe occurrence of middle interhemispheric variants inHPE cases linked to ZIC2 mutations. Because dorsalstructures are primarily affected, effects on ventralstructures, such as hypotelorism and lack of forma-tion of the medial aspects of the hypothalamus andcaudates (morphologic characterisics of more classicforms of HPE [6]) are less likely. Indeed, presumablybecause Zic2 is involved in the differentiation of theroof plate and not of the floor plate, the craniofacialstructures are not malformed in mice with Zic2-re-

lated HPE (14), nor in humans with ZIC2-relatedHPE (13). Our findings of above average IODs orhypertelorism in all 21 patients further support thisdifference from classic HPE. Also, because effects ofZIC2 deficiency may occur segmentally along the ros-trocaudal axis of the neural tube, cases with MIH mayrepresent instances in which the midportion of theforebrain was selectively vulnerable to the geneticdefect. In future studies, it will be important to verifythese conclusions by correlating the phenotypic ef-fects in HPE with genetic and other bases.

It is intriguing to note that Zic2 is associated withneural tube closure, the failure of which may result incephalocele, myelomeningocele, or Chiari II malfor-

mation, and that cephaloceles and Chiari II malfor-mations were both present in some of our cases. Webelieve the presence of these associated malforma-tions further strengthens the likely association be-tween ZIC2 and MIH. Indeed, it was our impressionthat patients with MIH had a higher incidence ofsubstantial cerebellar anomalies (such as Chiari mal-formations) than those with classic HPE. In our ex-perience, approximately 10% of patients with classicHPE have an associated cerebellar abnormality andmost (80%) are mild inferior vermian hypogenesis(Simon EM, unpublished data).

The abnormal sylvian fissures, with their abnormalangulation and communication across the midline

over the vertex seems to have been previously re-ported. One report labeled this finding as a connect-ed transhermispheric cleft of focal cortical dysplasiain a patient with HPE (2). A review of the imagespublished in their case report reveals multiple vascu-lar branches in the sulcus. We believe that these arebranches of the middle cerebral arteries, which wouldclearly show these as extensions of the sylvian fissures.

Another report (5) of a nearly identical case de-scribed two siblings with fused schizencephalic cleftsin their bilateral frontal lobes. A similar finding waspresent in the images accompanying the case re-

FIG 6. Illustration of roof plate differentiation, which depends

on ZIC2 function.After neural tube closure (left), ZIC2 promotes differentiation of

the embryonic roof plate (rp) in the dorsal midline of the neuraltube. Normally, a low rate of mitotic activity and a high rate ofapoptosis in the roof plate of the forebrain contribute to inter-hemispheric cleavage (upper right). If one ZIC2 allele is mutant(ZIC2/-), differentiation of the roof plate is compromised, re-sulting in HPE (lower right).

cx indicates cortex; ey, eye; fp, floor plate; hy, hypothalamus;st, striatum.

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ported by Robin et al (4), but the authors did notspecifically mention this component of the malforma-tion. By reviewing images from a larger series of MIHpatients, we were able to identify this pattern consis-tently and realize that the sulci are extensions of thesylvian fissures and are common structural character-istics of MIH.

Our review of the literature also revealed case

reports that were described as lobar HPE, but re-view of the published figures or pathologic descrip-tions suggests that these were cases of MIH (15, 16).

An intact anterior IHF can be identified in the imagespresented, and the deep gray nuclear and ventricularconfigurations closely resemble those seen in our se-ries (15). These two cases have been reported as aconstellation of HPE, hypertelorism, and ectrodac-tyly. To our knowledge, our patients with MIH andhypertelorism did not have anomalies of their hands.

The advances of modern medicine allow patientswith severe brain malformations to survive infancy,often into late childhood and adulthood. Therefore, itis useful to be able to diagnose brain malformations

and prognosticate developmental potential of af-fected infants. Accurate diagnosis allows propercounseling of parents and preparation of caregiversand parents for the future needs of the child. Corre-lation of specific morphologic features of these anom-alies with outcome may allow identification of specificfeatures that make such prognostication possible.Thus, such detailed analysis of structural features ofdysmorphic brains may allow prognostication and elu-cidate potential embryogenetic mechanisms. Futureinvestigations are planned to correlate these morpho-logic abnormalities with specific clinical features andgenerate more accurate prognostic information.

Conclusion

Our analysis of these MIH patients further refinesthe morphologic spectrum of this disorder and fur-ther contrasts it with the structural characteristics ofclassic HPE. These morphologic differences allowfurther elucidation of the embryologic differences be-tween the two malformations, one likely resulting

from the disturbances of formation of the embryonicfloor plate (classic HPE) and the other of the roofplate (MIH). Future correlation of the morphologicdata with clinical and neurodevelopmental informa-tion may help to provide more accurate prognosticinformation to families of patients with MIH.

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